Five years after specializing in pediatric emergency medicine, Dr. Richard Strait took an academic position in this specialty at Cincinnati Children's Hospital Medical Center and initiated research in anaphylaxis, an area pertinent to emergency medicine, with Dr. Fred Finkelman as mentor. Although this research has been productive, Dr. Strait, Dr. Finkelman, and Dr. Strait's supervisors at CHMC realize that additional training in Immunology and Molecular Biology will be required for Dr. Strait to develop into an independent investigator. Consequently, a four year training program has been designed that will allow Dr. Strait to attend journal clubs, research conferences, and formal classes in Immunology and Molecular Biology and to continue his training in laboratory research under Dr. Finkelman, using studies of anaphylaxis as a vehicle for this training. Anaphylaxis is important both as a disease and as a physiological mechanism: the cellular processes that cause anaphylactic shock are systemic exaggerations of processes central to both allergic pathophysiology and host defense against gastrointestinal nematode parasites. The cytokine IL-4 contributes to anaphylaxis by promoting IgE and IgG1 responses and mast cell proliferation. Recently, Dr. Strait discovered that IL-4 has an additional important effect: it sensitizes animals to stimuli that cause anaphylaxis, so that a stimulus that causes a mild anaphylactic reaction in the absence of IL- 4 will cause lethal anaphylaxis in the presence of IL- 4. This proposal will characterize this novel effect of IL-4. Experiments will determine: 1) the dose-response and kinetics of the IL-4 effect; 2) the ability of endogenously produced IL-4 to enhance anaphylaxis, 3) the signaling pathway involved in IL- 4 enhancement of anaphylaxis and 4) whether IL-4 enhances anaphylaxis by increasing mediator release and/or by increasing responsiveness to released mediators. In addition to providing basic information about the pathogenesis of anaphylaxis and the mechanisms by which IL-4 contributes to both allergy and protective immunity, results of these experiments should suggest how IL-4 antagonists could best be used to treat allergic disorders